Editors' ChoiceHost-Pathogen Interactions

Painful Subversion of the Host Defense

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Sci. Signal.  10 Sep 2013:
Vol. 6, Issue 292, pp. ec213
DOI: 10.1126/scisignal.2004713

Bacterial infections cause the classical response of redness, swelling, heat, and pain. Vasodilation and the recruited immune cells contribute to each of these (see Nizet and Yaksh). Chiu et al. found that both live and heat-killed bacteria caused direct activation of nociceptive neurons and induced hyperalgesia in mice. Using infection of mouse hindpaws as a model, mechanical, cold, and heat hypersensitivity correlated best with the bacterial load of Staphyloccocus aureus infection and not with tissue swelling, immune cell recruitment, or the concentrations of proinflammatory cytokines that sensitize nociceptive neurons. Infection-induced hyperalgesia was not reduced in mice genetically compromised in Toll-like receptor (TLR) signaling or lacking T and B cells. However, mice engineered to lack nociceptive neurons failed to exhibit mechanical or thermal hypersensitivity to S. aureus infection, despite exhibiting increased swelling, immune cell infiltration, and lymphadenopathy of the closest lymph node when compared with infected wild-type mice. Application of live or heat-killed S. aureus or six other heat-killed bacteria to mouse dorsal root ganglia activated calcium signals. Detailed analysis of the responses to S. aureus showed that action potentials were induced in capsaicin-responsive nociceptive neurons. Bacteria produce N-formylated peptides, and one such peptide from Escherichia coli or one from S. aureus stimulated calcium influx in a subset of capsaicin-responsive neurons. Calcium influx in response to the S. aureus peptide was reduced in dorsal root ganglia from mice genetically deficient in the receptor for N-formylated peptides (Fpr). Fpr-knockout mice also exhibited less hyperalgesia to mechanical stimuli when injected with either the peptide or heat-inactivated S. aureus. Bacteria also secrete virulence factors that include various toxins. S aureus secretes α-haemolysin (α-HL), which elicited pain behavior in mice and stimulated calcium influx and action potentials in capsaicin-responsive neurons in dorsal root ganglia. The response to α-HL activity in dorsal root ganglia was abolished by heating the toxin or when a mutant that could not form oligomers and thus could not form pores was used. Injection of a strain of S. aureus lacking α-HL caused less hyperalgesia than injection of strains that produced the toxin. Because mice lacking nociceptive neurons exhibited a reduced immune response to S. aureus infection, possible mechanisms by which these neurons communicated to the immune system were explored. Receptors for the neuropeptides CGRP, galanin, and somatostatin, which were found to be abundant in nociceptive neurons, were detected in immune cells. These neuropeptides inhibited proinflammatory cytokine release when added to macrophages in culture that had been exposed to heat-killed S. aureus. Injection of CGRP during S. aureus infection reduced lymphadenopathy of the draining lymph nodes. Thus, bacterial products can directly stimulate pain by activating neurons, which in turn produce signals that suppress the immune response, establishing another mechanism by which pathogens subvert the host defenses in a particularly painful manner.

I. M. Chiu, B. A. Heesters, N. Ghasemlou, C. A. Von Hehn, F. Zhao, J. Tran, B. Wainger, A. Strominger, S. Muralidharan, A. R. Horswill, J. B. Wardenburg, S. W. Hwang, M. C. Carroll, C. J. Woolf, Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013). [PubMed]

V. Nizet, T. Yaksh, Bacteria get on your nerves. Nature 501, 43– 44 (2013). [PubMed]